Modeling the active site of β-secretase: Application to drug discovery


Ramkumar Rajamani, Computer-Aided Drug Discovery, Johnson and Johnson PRD LLC, PO BOX 776, Welsh and McKean Rd, Spring House, PA 19477 and Charles H. Reynolds, Molecular Design and Informatics, Johnson & Johnson Pharmaceutical Research and Development L.L.C, Welsh and McKean Roads, PO Box 776, Spring House, PA 19477.
The cleavage of β-amyloid precursor protein (APP) by β-Secretase (BACE) is a crucial step in the production of the β-amyloid peptide that has been implicated as a probable cause of Alzheimer’s disease (AD). This has made BACE an attractive therapeutic target for treatment of AD. There are two aspartic acid residues (Asp 32 and Asp 228) in the catalytic region of BACE that can adopt multiple protonation states and tautomers. The protonation state and precise location of the protons for these two residues, particularly in the presence of an inhibitor, have a direct bearing on efforts to model this system properly. In the present study, we have carried out full quantum mechanical calculations using a linear scaling quantum mechanical method to identify the preferred protonation states and proton locations for Asp 32 and Asp 228 in the presence of inhibitors. Additionally, a binding affinity model based on the LIE approach has been developed that is capable of rank ordering inhibitors of BACE.

Docking and Scoring
1:30 PM-5:20 PM, Sunday, August 22, 2004 Pennsylvania Convention Center -- 109B, Oral

Division of Computers in Chemistry

The 228th ACS National Meeting, in Philadelphia, PA, August 22-26, 2004